The invention relates to a method for producing powdered pharmaceutical compositions. More specifically, the invention relates to a method for forming dense, substantially solid particles from pharmaceutical compositions, where the particulate compositions are particularly suitable for transdermal particle delivery from a needleless syringe system.
The ability to deliver pharmaceuticals through skin surfaces (transdermal delivery) provides many advantages over oral or parenteral delivery techniques. In particular, transdermal delivery provides a safe, convenient and noninvasive alternative to traditional drug administration systems, conveniently avoiding the major problems associated with oral delivery (e.g., variable rates of absorption and metabolism, gastrointestinal irritation and/or bitter or unpleasant drug tastes) or parenteral delivery (e.g., needle pain, the risk of introducing infection to treated individuals, the risk of contamination or infection of health care workers caused by accidental needle-sticks and the disposal of used needles).
However, despite its clear advantages, transdermal delivery presents a number of its own inherent logistical problems. The passive delivery of drugs through intact skin necessarily entails the transport of molecules through a number of structurally different tissues,including the stratum corneum, the viable epidermis, the papillary dermis, and the capillary walls in order for the drug to gain entry into the blood or lymph system. Transdermal delivery systems must therefore be able to overcome the various resistances presented by each type of tissue. In light of the above, a number of alternatives to passive transdermal delivery have been developed. These alternatives include the use of skin penetration enhancing agents, or xe2x80x9cpermeation enhancers,xe2x80x9d to increase skin permeability, as well as non-chemical modes such as the use of iontophoresis, electroporation or ultrasound. However, these alternative techniques often give rise to their own unique side effects, such as skin irritation or sensitization. Thus, the spectrum of pharmaceuticals that can be safely and effectively administered using traditional transdermal delivery methods has remained limited.
More recently, a novel transdermal drug delivery system that entails the use of a needleless syringe to fire powders (i.e., solid drug-containing particles) in controlled doses into and through intact skin has been described. In particular, commonly owned U.S. Pat. No. 5,630,796 to Bellhouse et al. describes a needleless syringe that delivers pharmaceutical particles entrained in a supersonic gas flow. The needleless syringe is used for transdermal delivery of powdered drug compounds and compositions, for delivery of genetic material into living cells (e.g., gene therapy) and for the delivery of biopharmaceuticals to skin, muscle, blood or lymph. The needleless syringe can also be used in conjunction with surgery to deliver drugs and biologics to organ surfaces, solid tumors and/or to surgical cavities (e.g., tumor beds or cavities after tumor resection). In theory, practically any pharmaceutical agent that can be prepared in a substantially solid, particulate form can be safely and easily delivered using such devices.
One particular needleless syringe generally comprises an elongate tubular nozzle having a rupturable membrane initially closing the passage through the nozzle and arranged substantially adjacent to the upstream end of the nozzle. Particles of a therapeutic agent to be delivered are disposed adjacent to the rupturable membrane and are delivered using an energizing means which applies a gaseous pressure to the upstream side of the membrane sufficient to burst the membrane and produce a supersonic gas flow (containing the pharmaceutical particles) through the nozzle for delivery from the downstream end thereof. The particles can thus be delivered from the needleless syringe at delivery velocities of between Mach 1 and Mach 8 which are readily obtainable upon the bursting of the rupturable membrane.
Another needleless syringe configuration generally includes the same elements as described above, except that instead of having the pharmaceutical particles entrained within a supersonic gas flow, the downstream end of the nozzle is provided with a bistable diaphragm which is moveable between a resting xe2x80x9cinvertedxe2x80x9d position (in which the diaphragm presents a concavity on the downstream face to contain the pharmaceutical particles) and an active xe2x80x9cevertedxe2x80x9d position (in which the diaphragm is outwardly convex on the downstream face as a result of a supersonic shockwave having been applied to the upstream face of the diaphragm). In this manner, the pharmaceutical particles contained within the concavity of the diaphragm are expelled at a supersonic initial velocity from the device for transdermal delivery thereof to a targeted skin or mucosal surface.
Transdermal delivery using either of the above-described needleless syringe configurations is carried out with particles having an approximate size that generally ranges between 0.1 and 250 xcexcm. For drug delivery, an optimal particle size is usually at least about 10 to 15 xcexcm (the size of a typical cell). For gene delivery, an optimal particle size is generally substantially smaller than 10 xcexcm. Particles larger than about 250 xcexcm can also be delivered from the device, with the upper limitation being the point at which the size of the particles would cause untoward damage to the skin cells. The actual distance which the delivered particles will penetrate depends upon particle size (e.g., the nominal particle diameter assuming a roughly spherical particle geometry), particle density, the initial velocity at which the particle impacts the skin surface, and the density and kinematic viscosity of the skin. In this regard, optimal particle densities for use in needleless injection generally range between about 0.1 and 25 g/cm3, preferably between about 0.8 and 1.5 g/cm3, and injection velocities generally range between about 100 and 3,000 m/sec.
It is a primary object of the invention to provide a spray-coated powder composition for administration from a needleless syringe. It is also a primary object of the invention to provide suitable spray-coating methods for producing such powder compositions.
In one aspect of the invention, a spray-coated powder composition for administration from a needleless syringe is provided. The powder composition is formed from seed particles that are coated with an aqueous pharmaceutical composition. More especially, the spray-coated powder composition comprises seed particles coated with a pharmaceutical composition, the said coated seed particles having an average size of about 10 to 100 xcexcm and having an envelope density ranging from about 0.1 to about 25 g/cm3.
The coated seed particles can have an average size of about 20 to 70 xcexcm. Preferably, they have an envelope density ranging from about 0.8 to about 1.5 g/cm3. The coated seed particles typically have a substantially spherical aerodynamic shape and/or a substantially uniform, nonporous surface. The powders may also be characterized in that the coated seed particles have a pharmaceutical composition loading of about 1 to 50 wt %. The spray-coated powder compositions can contain, as the active pharmaceutical agent, any small molecule drug substance, organic or inorganic chemical, vaccine, or peptide (polypeptide and/or protein) of interest.
In another aspect of the invention, a method for preparing the spray-coated powder composition is provided. The method comprises spray-coating an aqueous pharmaceutical composition onto seed particles under conditions sufficient to provide coated particles having an average size of about 10 to 100 xcexcm and an envelope density ranging from about 0.1 to about 25 g/cm3. In one particular embodiment, the method entails the steps of: (a) suspending the seed particles in a reaction chamber using a hot air flow; (b) atomizing an aqueous pharmaceutical composition into a fine spray and introducing the spray into the reaction chamber; (c) allowing the spray to spread over the surface of the suspended seed particles to coat them with a thin film; and then (d) drying the coated seed particles. If desired, the aqueous pharmaceutical composition can be sprayed into the reaction chamber in a direction that is transverse to the direction of the hot air flow.
It is an advantage of the invention that free-flowing powder compositions can be produced having well defined particle size, density and mechanical properties which collectively are suitable for transdermal delivery from a needleless syringe. Further advantages of the methods of the invention include flexible pharmaceutical loading (up to about 50 wt %), overall process efficiency (no need for post-formulation fractionation, classification or sieving operations), and the methods are readily scalable. The invention further provides:
a dosage receptacle for a needleless syringe, said receptacle containing a therapeutically effective amount of a spray-coated powder composition of the invention; and
a needleless syringe which is loaded with such a powder composition.
These and other objects, aspects, embodiments and advantages of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein.